N-acetyl neuraminic acid (sialic acid) is a common constituent of many macromolecular compounds, especially the polysaccharide chains of glycoproteins and ganliosides. Knowledge of structure and metabolism of these compounds has been materially aided through the study of mutations expressed lysosomal storage diseases. The incompleteness of our understanding of the metabolism of neuraminic acid containing compounds is in part related to the lack of recognition of a lysosomal storage disease occurring secondary to a deficiency of lysosomal neuraminidase (EC 3.2.1.18). We have followed since birth a presently seven month old female with clinical features of a lysosomal storage disease. Electron microscopy of a bone marrow aspirate and cultured skin fibroblasts demonstrated single membrane bound cytoplasmic vacuoles consistent with a lysosomal storage disease. Extensive biochemical analyses of cultured skin fibroblasts failed to establish the diagnosis of a known lysosomal enzyme deficiency. Her phenotype suggested a unique disorder. Assay of neuraminidase revealed no detectable activity at pH 4.2 but normal activity at pH 6. Measurement of intracellular sialic acid revealed normal levels of free sialic acid but a tenfold increase in the level of bound sialic acid. Her obligate heterozygous parents had intermediate levels of enzyme activity. Based on these findings one would predict a phenotype similar to that with lysosomal storage of the oligosaccharides of glycoproteins such as fucosidosis or mannosidosis and/or lysosomal storage of gangliosides such as GM1 or GM2 gangliosidosis. At present distinctive features on none of these disorders are apparent. We propose to undertake a detailed study of the evolution of the phenotype in this unique disorder and biochemical studies to determine the nature of the storage material(s).